Obesity is among the most challenging health problems confronting developed countries due to its association with metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular disease. Obesity is remarkably common, affecting >1/3rd of US adults, but is very challenging to treat due to the inexorable regain of los weight. Since body fat stores are subject to homeostatic regulation in both lean and obese subjects, the failure of obesity therapy over time likely represents the defense of an elevated level of body fat mass. Our recent findings implicate neuron injury and surrounding gliosis in key hypothalamic areas for body weight control as a significant contributory mechanism to obesity pathogenesis. Specifically, we observed a rapid accumulation of reactive astrocytes and microglia in the mediobasal hypothalamus during the initiation of high fat diet consumption in rodents concomitant with cellular stress responses in surrounding energy homeostasis- regulating neurons. Our K08 proposal focused on the contribution of hypothalamic microglia to obesity- associated inflammation and injury. In this proposal, we extend these ongoing investigations to focus on metabolic coupling between hypothalamic astrocytes and neurons. Astrocytes contain glycogen stores that are mobilized to provide lactate to surrounding neurons during times of increased synaptic activity. We have recently determined that acute blockade of hypothalamic astrocyte glycogenolysis promotes food intake, and that obese rodent models contain increased hypothalamic accumulations of astrocyte glycogen. These data support the premise that disruption of metabolic coupling between hypothalamic astrocytes and neurons contributes to obesity pathogenesis. We will investigate this hypothesis by determining the specific hypothalamic nuclei involved in food intake-triggered lactate utilization, whether diet composition and metabolic status affect hypothalamic lactate production, and the extent to which defective astrocyte glycogenolysis is necessary and sufficient for the development of obesity. The data obtained from these investigations will form the basis of a new line of research centered on glial-neuronal metabolic coupling as a novel obesity target.